The overall objective of this proposal is to understand the molecular mechanism of neurofibrillary degeneration of abnormally hyperphosphorylated tau protein and, based on this knowledge, identify specific therapeutic targets for Alzheimer disease (AD), Down syndrome and other tauopathies which are characterized by this brain lesion. The activity of protein phosphatase (PP)-2A, which regulates phosphorylation of tau, is in turn regulated partly by its inhibitor I2PP2A. In a large percentage of neurons in AD brain, I2PP2A is translocated from its primary localization in the nucleus to the cytoplasm. As PP-2A and tau are localized in the cytoplasm, the increased cytoplasmic localization of I2PP2A in AD brain explains the inhibition of PP-2A, tau hyperphosphorylation and formation of neurofibrillary tangles. We propose (1) to investigate the molecular mechanism which controls the nuclear vs. cytoplasmic localization of I2PP2A in normal neurons. The transport factors (karyopherins) that mediate the import and export of I2PP2A into and out of the nuclei, and the I2PP2A domains which interact with these factors will be identified;(2) to elucidate the cause(s) of modified neuronal I2PP2A localization in Alzheimer's disease. We will investigate the effect of the cleavage of I2PP2A, which occurs in AD brains, on the I2PP2A interaction with the transport factors. We will also investigate the effects of the interactions of I2PP2A with other soluble and fixed proteins on I2PP2A localization in normal and AD brain, and the role of I2PP2A phosphorylation;(3) to generate transgenic mice which express the N-terminal half I2PP2A (observed in the cytoplasm of neurons in the AD brain) or a control variant of this protein localized in the nuclei, under the control of an inducible expression system. The effect of these transgenes on PP-2A activity, the activities of tau kinases regulated by PP-2A and abnormal hyperphosphorylation of tau, and as well as neurodegeneration and cognitive impairment, will be studied. These studies will lead to the elucidation of the mechanism of neurofibrillary degeneration and to the identification of one or more therapeutic targets. The studies will lead also to the generation of a cellular and an animal model of tauopathies, which can be used for the development of therapeutic drugs for diseases characterized by this lesion.